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Triggering the resolution of immune mediatedinflammatory diseasesHopkin, Sophie; Lewis, Jonathan; Krautter, Franziska; Chimen, Myriam; McGettrick, Helen
DOI:10.3389/fphar.2019.00184
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Citation for published version (Harvard):Hopkin, S, Lewis, J, Krautter, F, Chimen, M & McGettrick, H 2019, 'Triggering the resolution of immunemediated inflammatory diseases: can targeting leukocyte migration be the answer?', Frontiers in Pharmacology,vol. 10, 184. https://doi.org/10.3389/fphar.2019.00184
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MINI REVIEWpublished: 01 March 2019
doi: 10.3389/fphar.2019.00184
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Queen Mary University of London,United Kingdom
Reviewed by:Michael Hickey,
Monash University, AustraliaDianne Cooper,
Queen Mary University of London,United Kingdom
*Correspondence:Helen M. McGettrick
†These authors have contributedequally to this work
‡These authors jointly coordinatedthis work
Specialty section:This article was submitted toInflammation Pharmacology,
a section of the journalFrontiers in Pharmacology
Received: 06 October 2018Accepted: 14 February 2019
Published: 01 March 2019
Citation:Hopkin SJ, Lewis JW, Krautter F,
Chimen M and McGettrick HM (2019)Triggering the Resolution of Immune
Mediated Inflammatory Diseases: CanTargeting Leukocyte Migration Be
the Answer?Front. Pharmacol. 10:184.
doi: 10.3389/fphar.2019.00184
Triggering the Resolution of ImmuneMediated Inflammatory Diseases:Can Targeting Leukocyte MigrationBe the Answer?Sophie J. Hopkin1†, Jonathan W. Lewis2†, Franziska Krautter1†, Myriam Chimen1‡ andHelen M. McGettrick2*‡
1 Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom, 2 Rheumatology ResearchGroup, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, Institute of Inflammationand Ageing, University of Birmingham, Birmingham, United Kingdom
Leukocyte recruitment is a pivotal process in the regulation and resolution of aninflammatory episode. It is vital for the protective responses to microbial infection andtissue damage, but is the unwanted reaction contributing to pathology in many immunemediated inflammatory diseases (IMIDs). Indeed, it is now recognized that patientswith IMIDs have defects in at least one, if not multiple, check-points regulating theentry and exit of leukocytes from the inflamed site. In this review, we will exploreour understanding of the imbalance in recruitment that permits the accumulation andpersistence of leukocytes in IMIDs. We will highlight old and novel pharmacologicaltools targeting these processes in an attempt to trigger resolution of the inflammatoryresponse. In this context, we will focus on cytokines, chemokines, known pro-resolvinglipid mediators and potential novel lipids (e.g., sphingosine-1-phosphate), along with theactions of glucocorticoids mediated by 11-beta hydroxysteroid dehydrogenase 1 and 2.
Keywords: leukocytes, migration, inflammation, resolution, PEPITEM, sphingosine-1-phosphate, glucocorticoids,11-beta hydroxysteroid dehydrogenase
INTRODUCTION
Acute inflammation is a self-limiting, resolving response in which leukocyte entry and exit istightly controlled. An imbalance in these processes permits accumulation and persistence ofleukocytes within inflamed tissue, leading to damaging chronic non-resolving inflammation thatunderpins immune-mediated inflammatory diseases (IMIDs). Although significant advances havebeen made, we still do not fully understand the physiological processes regulating resolution ofinflammation, and whether tissue-specific, or stimuli-specific processes exist. Current therapeuticstrategies target leukocytes directly or their cytokine products, and hence the activation process ofinflammation, rather than promoting resolution. Identifying the immune components that activelyinduce resolution of inflammation may be the key to novel therapeutic strategies for the treatmentof IMIDs (Fullerton and Gilroy, 2016). In this review, we will focus on the pharmacological toolsthat influence the migration of leukocytes during an inflammatory response and whether suchagents can trigger resolution (Figure 1).
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LEUKOCYTE TRAFFICKING IN HEALTH
Upon inflammation, blood vascular endothelial cells (EC) up-regulate adhesion molecules and chemokines necessary tosupport dynamic EC-leukocyte interactions and allow leukocytesto cross the EC barrier (Nourshargh and Alon, 2014; Melladoet al., 2015). The leukocytes themselves receive a series ofsequential signals as they negotiate this barrier, which influencetheir adhesive and migratory properties, effector functions (Luoet al., 2015) and survival (Filer et al., 2006; McGettrick et al.,2006) at the inflamed site. At the blood-tissue interface, selectivitybetween neutrophils and T-cells arises from the production anduse of specific capture receptors (E-, P-selectins, low affinityα4β1-integrin), adhesion molecules (β2-, β1-integrins bindingICAM-1 or VCAM-1, respectively), chemokine and junctionalmolecule combinations (Reglero-Real et al., 2016). Tissue-specific“address-codes” (Parsonage et al., 2005) are created by theinteractions of tissue-resident stromal cells with neighboring EC(McGettrick et al., 2012) and provide an extra level of complexityto the leukocyte adhesion cascade, controlling the number andtype of leukocytes recruited during a given inflammatory event.
CHRONIC INFLAMMATION:DYSREGULATION OF TRAFFICKING
Growing evidence indicates that leukocyte entry into, migrationthrough and exit from peripherally inflamed tissues is changedto some degree in patients with IMIDs, and that these processescan differ between individual’s with the same clinical diagnosis,and over the life-time of disease [i.e., amongst different phasesof disease, following therapeutic intervention; (Buckley andMcGettrick, 2018)]. Susceptibility genes associated with IMIDshave been shown to directly influence leukocyte recruitment andmigration. For instance, expression of the rheumatoid arthritis(RA) susceptibility variant of PTPTN22 (R620W) has beenreported to increase the adhesive and migratory properties ofmurine T-cells (Burn et al., 2016) and human neutrophils (Bayleyet al., 2015) in non-diseased models and subjects. Similarlyalterations in the cellular metabolism of leukocytes [namelyT-cells in RA (Shen et al., 2017) or monocytes in atherosclerosis]can render these cells hypermotile or overtly pro-inflammatory(Chimen et al., 2017). Additionally vascular EC from chronicallyinflamed tissues acquire pathogenic traits, including elevatedexpression of adhesion molecules (Jones et al., 1995; Salmi et al.,1997; Cañete et al., 2007). For instance, cultured rheumatoidsynovial EC required minimum TNFα stimulation to recruitleukocytes (Abbot et al., 1999). Similarly, secretory smoothmuscle cells associated with atherosclerotic plaques are ableto prime neighboring blood vascular EC to recruit leukocytesin response to very low TNFα concentrations (Rainger andNash, 2001). Pathogenic rheumatoid synovial fibroblasts overtlyactivate EC, leading to the inappropriate influx of leukocytes(Lally et al., 2005; Smith et al., 2008; McGettrick et al., 2009).These interactions evolve with the progression of RA (Fileret al., 2017). This will ultimately change the phenotype of EC(McGettrick et al., 2015) and therefore the types of leukocytes
they recruited as the disease persists. Thus it is clear that IMIDsadversely affect key cellular components that control leukocytemigration. Whilst we currently are unable to modify the geneticbackground of a patient with IMIDs, targeting environmentalalterations in key cellular components to trigger resolutionpathways is a much needed strategy.
TRIGGERING RESOLUTION OFIMMUNE-MEDIATED INFLAMMATORYDISEASES
In humans, it is difficult to evaluate the impact of current IMIDtherapies on the process of leukocyte trafficking, with manystudies only commenting on the changes in cell numbers in onetissue. A reduction in leukocyte numbers at an inflamed sitedue to drug treatment could arise from (i) reduced entry, (ii)enhanced clearance, (iii) promotion of exit, or (iv) retention inlymph nodes or other peripheral tissues that result in reducednumbers of leukocytes in the circulation (e.g., S1P inhibitors– see below). Indeed, anti-cytokine therapies systemically targetkey molecules utilized during leukocyte trafficking, includingEC activation (TNFα, IL-1β) or EC-stroma crosstalk (e.g.,IL-6). Raising the question – what properties should a pro-resolving agent have? If we specifically focus on the context ofleukocyte trafficking, potential modes of action would include,limiting cellular infiltration; inducing apoptosis; modulatingchemokine and cytokine gradients to promote egress andclearance; reprogramming of leukocytes (e.g., macrophage)phenotypes to induce suppressor cells and induction of tissuerepair mechanisms (Sugimoto et al., 2016a).
CytokinesThe cytokine pathways promoting resolution are largelyundefined thus far. Certain cytokines are considered to be anti-inflammatory, such as IL-10 and TGF-β, but does this mean theyalso induce resolution? IL-10 signaling caused the destabilizationof TNFα and IL-1α mRNA, thereby reducing protein productionin macrophages (Schaljo et al., 2009). Similarly, TGF-β caninhibit the translation of TNFα mRNA into protein in LPS-stimulated murine macrophages in vitro (Bogdan et al., 1992).Reduced TNFα levels at inflamed sites, as seen in patientstreated with TNFα inhibitors, causes EC and stromal cells torevert to a resting-like phenotype, downregulating the expressionof adhesion molecules and chemokines necessary to supportleukocyte migration (Tak et al., 1996). Mice deficient in eitherIL-10 (Keubler et al., 2015) or TGF-β1 (Kulkarni and Karlsson,1993; Dang et al., 1995; Letterio et al., 1996) have increasedsuspectibility to developing IMIDs. However, neither cytokineappeared to induce resolution when administered therapeuticallyin rodent models of IBD (Herfarth et al., 1998; Barbara et al.,2000; Kitani et al., 2000); and only TGF-β was shown to reduceleukocyte infiltration and disease severity (Kitani et al., 2000).Raising the question as to whether these cytokines can influencethe migration of leukocytes to support resolution. IL-10 therapyhas been reported to reduce the incidence of psoriasis relapsein a cohort of patients in remission (Friedrich et al., 2002),
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FIGURE 1 | Regulation of leukocyte trafficking as a way to enhance resolution. Leukocytes, such as neutrophils, monocytes, and lymphocytes, are recruited to andmigrate through the vessel wall to reach the site of inflammation. This process is tightly regulated and involves adhesion molecules and chemokine-chemokinereceptor signal transduction, as well as interaction with the stromal compartment. Critically, these processes become dysregulated in chronic inflammatory diseasesleading to aberrant recruitment that contributes to the diseases. There is a growing interest in finding ways to control leukocyte trafficking as a means to reduce thenumbers of leukocyte in inflammatory sites, and therefore potentially allow resolution. Amongst those potential targets are cytokines, such as IL-10 and TGF-β; lipidmediators (e.g., lipoxins, resolvins, maresin-1, and S1P); annexin A1, glucocorticoids and its regulating enzyme 11β-HSD-1, as well as the recently characterizedpChemokines and ACKRs. These potential targets are all capable of modulating leukocyte migration and further investigation is required to establish their potentialpro-resolution roles.
and induce clinical remission in ∼25% of patients with steroid-resistant Crohn’s disease when compared to placebo control(van Deventer et al., 1997). Whilst both cytokines modulateinflammation, their clinical potential as pro-resolving therapieshas yet to be fully determined.
ChemokinesChemokines are active regulators of leukocyte migration intoand out of tissues, as well as playing a key role in thepositioning of leukocytes within the inflamed site. The successesand failures of targeting the chemokine pathway to blocktheir pro-inflammatory functions and interfere with leukocytemigration has been reviewed elsewhere (Asquith et al., 2015).Recently, an alternative means of targetting chemokines to induceresolution was described: pChemokines are short-chain peptideswith high affinity for chemokine glycosaminoglycan binding do-main, which enables them to act as competitive inhibitors forchemokine receptors (McNaughton et al., 2018). pCXCL8 treat-ment was able to reduce neutrophil migration across CXCL8-treated endothelium in vitro and limited the numbers of leukocy-tes infiltrating arthritic murine joints (McNaughton et al., 2018).
pChemokines are potentially a promising new therapeutic optionfor IMIDs, limiting the inflammatory infiltrate. It remains tobe seen whether pChemokines also display other pro-resolvingmechanisms, such as inducing tissue repair or reprogramming ofmacrophages from classical to alternative activation.
Endogenous removal of chemokines, either by drainagethrough the lymphatics or by chemokine-scavenging atypicalchemokines (ACKRs), is necessary to facilitate the removal ofthe inflammatory infiltrate during resolution (Bonecchi andGraham, 2016). The potential role of ACKRs in resolutionhas been reviewed elsewhere (Bonecchi and Graham, 2016).As an example, ACRK2 (also known as D6) deficient micehave increased chemokine expression in the kidney (Bideaket al., 2018) and skin (Jamieson et al., 2005), accompanied byaccumulation of T-cells in these tissues and exacerbation ofnephrotoxic nephritis and psoriasis. To date, it is unclear whetherthe functional properties of ACKR2 can be defined as pro-resolving rather than anti-inflammatory, and whether ACKR2has utility as a therapeutic target. Nevertheless, it is possiblethat agents that manipulate the expression and/or sequesteringproperties of ACKRs may be able trigger the resolution
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process in patients with IMIDs. Further work in this areais urgently required.
Bioactive Pro-resolving Mediators –Resolvins, Lipoxins, Protectins,Maresin and Annexin A1A variety of bioactive lipid mediators and proteins with pro-resolving properties have been identified, including lipoxins,resolvins, protectins and maresins (Serhan and Petasis, 2011),and subsequently shown to become dysregulated in patientswith IMIDs contributing to pathology (Serhan, 2014; Brouwerset al., 2015). Circulating cytokine and chemokine levels canbe directly modulated by such agents – for instance maresincan reduce IL-6, IL-1β (Marcon et al., 2013), and CCL2 levels(Martínez-Fernández et al., 2017), whilst annexin A1 (alsoknown as lipocortin) is able to increase IL-10 production(Martínez-Fernández et al., 2017). Moreover, annexin A1,resolvins D1 and D2, and lipoxin A4 can all inhibit theexpression of selectin molecules [e.g., P-selectin (Scalia et al.,1997), E-selectin (Chatterjee et al., 2014), or trigger L-selectinshedding (Strausbaugh and Rosen, 2001)] and also reduceβ-integrin affinity states and their ability to cluster (Spiteet al., 2009; Krishnamoorthy et al., 2010; Drechsler et al.,2015) on both leukocytes and on the endothelium. Reducedexpression, activation and clustering of adhesion molecules,along with increased shedding will have considerable impact onthe leukocyte recruitment cascade. Indeed, substantial evidenceexists that pro-resolving lipid mediators, such as annexin A1,maresin-1, lipoxin A4, resolvin E1 and protectin D1 can inhibitneutrophil or monocyte infiltration into a variety of inflamedtissues, including mesentery (Lim et al., 1998), gut (Schwabet al., 2007), lung (Guido et al., 2013; Gong et al., 2014), brain(Gavins et al., 2012), atherosclerotic lesions (Drechsler et al.,2015), to promote resolution. Protectin D1, and to a lesser extentresolvin E1, are also able to enhance neutrophil and macrophageegress from inflamed cavities to neighboring lymphoid tissues(lymph node/spleen), further facilitating resolution through theremoval of the microbial challenge via the lymphatics (Schwabet al., 2007). For further details, this topic is reviewed in depthelsewhere (Ortega-Gómez et al., 2013; Headland and Norling,2015; Sugimoto et al., 2016b). Such data would indicate that theseagents offer the potential to induce resolution in patients withIMIDs; however, the clinical efficacy of these agents has yet tobe proven.
Sphingosine-1-PhosphateNumerous pharmaceutical companies are currently interestedin modifying the bioactivity of sphingosine-1-phosphate (S1P)(Dyckman, 2017), yet it remains unclear whether S1P functionsas a pro-resolving or a pro-inflammatory lipid mediator. Themost abundant store of S1P is found in the blood, where themajority is bound to plasma proteins reducing its bioavailability(Christoffersen et al., 2011). The two main consequences ofthis are: (i) a S1P concentration gradient between the bloodand tissue (Pappu et al., 2007) and (ii) reduced S1P receptor(SIPR) expression on circulating leukocytes (Lo et al., 2005).
However, re-expression of surface S1PR1 and S1PR4 is stimulatedby chemokine-induced integrin activation of T-cells bound toinflamed blood vascular EC, sensitizing these cells to S1P (Chimenet al., 2015). Under these circumstances, locally released S1P wasable to inhibit T-cell transendothelial migration, by reducing theaffinity state of β2-integrins from high to low (Chimen et al.,2015). In this study, B-cells recruited to the inflamed EC andbinding adiponectin secrete a novel 14 aa immunomodulatorypeptide, called PEPITEM (PEPtide Inhibitor of TransendothelialMigration) (Chimen et al., 2015). PEPITEM binds to cadherin-15 on the endothelium triggering S1P production and releasethrough the S1P transporter, SPSN2 (Chimen et al., 2015).
The inability to produce PEPITEM, and thus stimulate localS1P production, contributes to the inappropriate accumulationof T-cells in inflamed tissues in type-1-diabetes and RA (Chimenet al., 2015). Thus in this context S1P acts in an anti-inflammatorymanner and could be an early initiator of the pro-resolvingmachinery. Mast cell derived S1P can also indirectly regulateleukocyte rolling triggering rapid mobilization of P-selectin tothe EC surface in a S1PR3 dependent manner in response totissue damage (Nussbaum et al., 2015). In a counter-regulatorymanner, leukocyte rolling was enhanced in S1PR1 deficientmice, indicating that S1PR1 is inhibitory for leukocyte rolling(Nussbaum et al., 2015). Thus the actions of S1P may be subtlymodified dependent on the different S1PR triggered.
In addition to regulating leukocyte entry into inflamedperipheral tissues, S1P has also been reported to influencethe transit through and exit from these sites across lymphaticendothelium (Ledgerwood et al., 2007). For instance, S1Preportedly enables activated CD4+ T-cells (OT-II cells) to persistand move about within inflamed ear pinnae when the cellsare injected directly into the tissue, whereby inhibiting S1Psignaling with fingolimod reduced the speed at which T-cellscells traveled within the ear (Jaigirdar et al., 2017). Moreover,fingolimod significantly reduced the number of activated T-cellsretained in the ear, suggesting that in the absence of S1P signalsthe activated T-cells were now able to migrated out of thetissue across the lymphatics (Jaigirdar et al., 2017). Similarly,S1P signaling through S1PR1 blocked T-cell migration acrosslymphatic endothelial cells of the footpad (Ledgerwood et al.,2007), strongly indicating that S1P signaling regulates T-cell exitof peripheral tissues. Overall it appears that S1P has dual roles inregulating leukocyte recruitment and migration, acting to bothpromote and inhibit it depending on context. The relationshipbetween these properties and the resolution processes remains tobe fully elucidated.
Dysregulation of S1P production, leading to higher S1P levelsin chronically inflamed tissues is a shared feature of many IMIDs.For example, elevated levels of the enzyme (SPHK-1) necessaryfor S1P synthesis have been reported in rheumatoid synovium(Jaigirdar et al., 2017) and ulcerative colitis (Karuppuchamy et al.,2017), whilst high concentrations of S1P occur in broncholavagefluid (Ammit et al., 2001) and cerebrospinal fluid (Kułakowskaet al., 2010) from asthma and multiple sclerosis (MS) patients.This tends to support the notion that the bioactivity of S1P is pro-inflammatory rather than pro-resolving. Indeed, inhibiting S1Psignaling with FTY720 has protective effects when administered
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therapeutically in rodent models of MS (Sheridan and Dev, 2014),inflammatory arthritis (Matsuura et al., 2000; Wang et al., 2007;Tsunemi et al., 2010; Fujii et al., 2012; Han et al., 2015), andsystemic lupus erythematosus (SLE) (Wenderfer et al., 2008).Moreover, fingolimod is an FDA-approved treatment for MS withclinical efficacy in reducing relapses in patients with relapsingremitting MS (Kappos et al., 2006; Singer, 2013), but not thosewith primary progressive MS (Lublin et al., 2016). Nevertheless,existing S1P modulators are known to induce lymphopenia(Wang et al., 2007; Tsunemi et al., 2010) by blocking lymphocyteexit from lymph nodes (Mandala et al., 2002; Chiba, 2005; Hanet al., 2015) – thus indirectly reducing the circulating numbersof cells available to enter peripherally inflamed sites. This canresult in a general immunosuppression in patients; increasingsusceptibility to opportunistic infections, whilst reducing vaccineefficiency (Massberg and von Andrian, 2006). Moreover, it ishighly probable that S1P modulators also interfere with the S1P-dependent migration of T-cell out of peripherally inflamed tissuesacross lymphatic endothelium (Ledgerwood et al., 2007), andthus maybe responsible for retention of cells at the inflamed sitefurther exacerbating disease.
11-Beta HSD Enzymes inRegulating GC FunctionGlucocorticoids (GCs) are steroid hormones responsible forregulating cellular metabolism, immune function, adhesionmolecule expression, and leukocyte migration (Tomlinsonand Stewart, 2001). Dexamethasone (a synthetic GC) reducedthe expression of E-selectin on inflamed aortic EC, disruptingneutrophil migration (Brostjan et al., 1997). By contrast,dexamethasone enhanced CXCL12-induced chemotaxis ofresting human T-cells in vitro (Ghosh et al., 2009). BlockingGC function with prophylactic administration of glucocorticoidreceptor (GR) antagonists exacerbated neutrophil infiltrationinto the synovial of carrageenan-induced monoarthritis inrats (Leech et al., 1998). GCs also influence cell viability,promoting neutrophil survival (Cox, 1995; Ruiz et al., 2002),whilst stimulating eosinophil apoptosis (Druilhe et al., 2003).Importantly, GCs can indirectly promote the resolution ofinflammation through the induction of annexin A1 on humanneutrophils and monocytes (Goulding et al., 1990). Annexin A1can disrupt neutrophil migration, causing adherent neutrophilsto detach from inflamed mesenteric endothelium and re-enterthe circulation (Lim et al., 1998) restoring tissue homeostasis.Synthetic GCs clearly elicit cell-type specific effects, elicitingmore immunomodulatory rather than immunosuppressiveeffects and may even exacerbate inflammation. Yet theyare commonly used to treat IMIDs [e.g., RA, MS, psoriasis(Coutinho and Chapman, 2011)], where prolonged useis associated with metabolic and endocrine dysregulation(Schäcke et al., 2002).
The predominately active GC in humans is cortisol, whichupon binding to the cytosolic GR, modifies gene expressionto promote an anti-inflammatory response (Schüle et al., 1990;De Bosscher et al., 1997). The local bioavailability of GC isregulated by metabolic enzymes, including the two isoforms of
11β-hydroxysteroid dehydrogenase [11β-HSD-1 and 11β-HSD-2;(Seckl and Walker, 2001; Tomlinson and Stewart, 2001)]. Residingin the lumen of the ER, 11β-HSD-1 primarily reduces cortisone(inactive GC) to cortisol (active GC) increasing local active GCconcentrations, whilst 11β-HSD-2 catalyzes the reverse reaction –inactivating cortisol and reducing active GC levels (Albistonet al., 1994; Seckl and Walker, 2001; Tomlinson and Stewart,2001). 11β-HSD-1 expression and activity are ubiquitious, albeitat varying amounts: high expression is found in GC-target tissues[e.g., liver and fat; (Seckl and Walker, 2001)] and much lowerlevels are seen in leukocytes (Thieringer et al., 2001; Chapmanet al., 2009; Coutinho et al., 2016). In contrast, 11β-HSD-2expression and activity are largely restricted to mineralocorticoid-target tissues, e.g., the kidneys, pancreas and large intestine(Albiston et al., 1994), and not found in leukocytes. Importantly,the expression and activity of 11β-HSD-1 is dynamically regulatedduring inflammation, where cytokines such as IL-1β (Sunand Myatt, 2003), IL-4 (Thieringer et al., 2001), and IL-13(Thieringer et al., 2001) induce 11β-HSD-1 activity stimulatinglocal increases in active GC which exert anti-inflammatory andpro-resolving effects. Interestingly, GC metabolism is skewedin patients with IMIDs, such as SLE (Ichikawa et al., 1997)and RA (Hardy et al., 2006), toward cortisol production andtherefore should trigger GC-induced anti-inflammatory/pro-resolving pathways to dampen the inflammatory response.However, despite elevated plasma cortisol levels in patients withIMIDs, the anti-inflammatory/pro-resolving GC pathways arenot obviously triggered. This discrepancy has been attributedto an insufficient levels of active GCs, as this deficiency can beovercome by administration of high-dose GC mimics to IMIDpatients (Straub and Cutolo, 2016). Thus the relationship betweenplasma cortisol and active GC is not strictly linear in chronicinflammation, opening avenues for further research into thedysregulation of GC metabolism.
11β-HSD-1 have also been reported to modulate leukocytetrafficking by influencing expression of chemokines and adhesionmolecules (Wamil et al., 2011; Kipari et al., 2013; Mylonas et al.,2017). However, in vivo studies blocking 11β-HSD-1 functionwith chemical agents or in 11β-HSD-1-deficient (Hsd11b1−/−)mice have reported conflicting findings. In a model ofacute thioglycollate-induced peritonitis in mice, augmentedleukocyte recruitment was observed following prophylacticinhibition of local 11β-HSD-1 (Coutinho et al., 2016) and inHsd11b1−/− mice (Coutinho et al., 2012). Similar findingswere reported in carrageenan-induced pleurisy (Coutinho et al.,2012) and coronary artery ligation induced myocardial infarction(McSweeney et al., 2010) in Hsd11b1−/− mice, supporting theconcept that 11β-HSD-1 functions to limit inflammation. Incontrast, lower amounts of MCP-1 were released by adipocytesfrom Hsd11b1−/− mice on a high fat diet, resulting in fewerCD8+ T-cell and macrophage infiltrating mesenteric adiposetissue (Wamil et al., 2011). Similarly low VCAM-1 expression byaortic endothelial cells was attributed to the significant reductionin T-cell and macrophage within atherosclerotic plaques ofHsd11b1−/− mice on high fat diet (Kipari et al., 2013). Thesestudies indicate that 11β-HSD-1 activity promotes leukocyterecruitment and hence inflammation. The field currently believes
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that the functional outcomes of 11β-HSD-1 activity, whetherthese be pro or anti-inflammatory, is governed by a mixtureof cell-specific, tissue-specific and inflammatory context-specificfactors. Therefore, it is impossible to say with any certainty that11β-HSD-1 has pro-resolving properties and is a viable drugtarget without further studies in this area.
That said, phase 2 clinical trials examining the efficacy of11β-HSD-1 selective inhibitors, such as INCB13739 in obesity-related inflammatory diseases are ongoing (Anagnostis et al.,2013), but as yet no candidate drug is in the pipeline for IMIDs.Nevertheless caution is required: 11β-HSD-1 down-regulators[e.g., glycyrrhizic acid and rosiglitazone (Mai et al., 2007; Wakeet al., 2007)] are associated with increased risk of cardiovascular-associated morbidity (Nissen and Wolski, 2007), hypertensionencephalopathy (Russo et al., 2000) and hypokalemic paralysis(Pant et al., 2010). Given the tissue-restricted expression patternsof 11β-HSD, there is growing excitement about the potentialto specifically modulate local GC concentrations using tissue-specific targeted therapies. However, we do not fully understandthe role of these enzymes in specific IMIDs. Critically, the effectsof endogenous GC and synthetic mimics are context dependentbased on cell-type and local environmental conditions creatinga complex interplay between GC, 11β-HSD enzymes and localenvironment, which is not yet fully understood. Clarifying therole of 11β-HSD enzymes in different IMIDs will allow the anti-inflammatory and pro-resolution properties that they exert to beexploited to promote the resolution of inflammation.
CONCLUSION AND CURRENTPERCEPTIONS
The regulated movement of leukocytes into, through and out ofperipheral tissues is vital in order to mediate tissue homeostasis
in response to an inflammatory insult. We are expanding ourunderstanding into how these processes are altered in thepathogenesis of IMIDs, and crucially the timing of such changesand their impact on the resolution of inflammation. With everystep forward, key agents with the capacity to induce resolutionand that may be amenable to therapeutic intervention becomeclearer. This represents an exciting new prospect that these noveldrugs would actively target endogenous regulatory processes toreduce leukocyte entry into tissues and promote their clearanceand egress to restore tissue homeostasis.
AUTHOR CONTRIBUTIONS
HM wrote the first draft of the manuscript. SH, JL, FK, andMC wrote sections of the manuscript. All authors contributed tomanuscript revision, read and approved the submitted version.
FUNDING
SH, JL, and FK were supported by MRC-Arthritis Research UK,Royal Society (RGF\R1\180008) and The Academy of MedicalSciences (SBF003\1156) funded Ph.D. studentships, respectively.MC was supported by a Royal Society Dorothy HodgkinResearch fellowship (DH160044) and HM was supported by anArthritis Research UK Career Development Fellowship (19899).Arthritis Research UK Rheumatoid Arthritis PathogenesisCentre of Excellence (RACE) was part-funded by ArthritisResearch UK (20298), this center is a collaboration betweenthe Universities of Glasgow, Newcastle, and Birmingham. MRC-Arthritis Research UK Centre for Musculoskeletal AgeingResearch (MR/P021220/1) is a collaboration between theUniversities of Birmingham, Nottingham, and Oxford.
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Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.
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Frontiers in Pharmacology | www.frontiersin.org 9 March 2019 | Volume 10 | Article 184
